Amyotrophic lateral sclerosis (ALS) is the classical form of motor neuron disease (MND). Like Alzheimer's disease (AD), ALS is a chronic progressive neuronal disorder that usually occurs in late life. Studies of ALS are relevant to AD for several reasons: subsets of ALS and AD patients have familial autosomal dominant disease linked to missense mutations of genes on chromosome 21; in both disorders, disease processes selectively affect groups of nerve cells; the mechanisms of selective vulnerability and dysfunction/death of these groups of neurons are not yet well understood in either disease; in ALS and AD, affected neurons develop cytoskeletal pathology and eventually die; these neuronal pathologies have been suggested to be mediated by several mechanisms, including excitotoxicity, oxidative damage, and calcium influx; with several exceptions, small animal models are not yet available; denervation sometimes occurs in subjects with ALS, and there are no effective therapies for ALS or AD. The Character, dynamics, and evolution of the cellular pathology and the mechanisms of cell dysfunction/death are difficult to study in humans. Because interventional biological approaches are not possible in humans and because autopsy analyses are usually limited to severe end-stage disease, animal models are essential. The recent discovery that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to familial ALS (FALS) suggest that transgenic strategies that introduce SOD1 mutations into mice can produce a model of FALS. These mice can be used to test the roles of these mutations in disease, to establish the characteristics and evolution of the pathology associated with these mutations, to clarify the mechanisms of motor neuron vulnerability and dysfunction, and to test novel therapies. In this Project, we will analyze the effect of the mutation on SOD1 activity in in vitro systems and on neurons in transgenic mice with SOD1 mutations. We will use strategies that have proven to be of great value in investigations of the mechanisms of dysfunction/death of neurons in other models of neuronal disease. We think that the approaches outlined in this Project to study transgenic mice with FALS mutations, which parallel those described in other projects of our Alzheimer's Disease Research Center, will greatly enhance our understanding of this neurodegenerative disease and will be of great value in identifying pathogenetic mechanisms and providing models to test therapies in late-onset, age-associated genetic diseases of the nervous system.